 |
|
 |
FDA Home Page | Search
FDA Site | FDA A-Z Index | Contact
FDA
Human Immunodeficiency Virus and
Acquired Immunodeficiency Syndrome
 |
FDA HIV/AIDS List Serve Archive
|
|
Today (12/31/2002) the Food and Drug Administration approved a new, extended
release formulation of ZERIT® (stavudine , d4T) called ZERIT® XR. This
extended-release formulation has been demonstrated to maintain measurable plasma
concentrations for 24 hours after once-daily dosing. ZERIT® XR is indicated
for the treatment of HIV in combination with other antiretrovirals. The recommended
dose of ZERIT XR is 100 mg once daily for individuals weighing at least 60 kg
and 75 mg once daily for individuals weighing less than 60 kg.
In a clinical study conducted in 783 treatment-naïve, HIV-infected individuals
ZERIT® XR was comparable to the previously approved twice daily formulation
of ZERIT. In this randomized, controlled study, participants were randomized
to either the extended release or standard formulation, in combination with
lamivudine and efavirenz. The proportion of patients with HIV-RNA (viral load
levels) below 400 copies/mL at 48 weeks was 79% and 76% for the extended release
and immediate release-containing regimens, respectively. For viral load under
50, the response rates were 55% and 57% for the new and old formulations, respectively.
The tolerability and safety profile of the new once daily, extended release
formulation is comparable to that of the previously approved twice daily formulation.
The study results were supported by a second, smaller study in 150 treatment naïve patients.
More convenient formulations, such as ZERIT® XR, may help patients with HIV more readily adhere to treatment regimens.
The full label will soon be available at the FDA website at http://www.fda.gov/cder/approval/index.htm Simply click "Z" in the index, and scroll to look for ZERIT® XR.
ZERIT XR is a product of the Bristol-Myers Squibb Company.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
On December 2, 2002, the HIV/AIDS Clinical Trials Information Service (ACTIS) and its sister service, the HIV/AIDS Treatment Information Service (ATIS), will be merged into a single website called AIDSinfo.nih.gov. The AIDSinfo project will include all of the services already available from ACTIS and ATIS, as well as added quick and easy access to wide-ranging Federal resources on HIV/AIDS clinical research, HIV treatment and prevention, and medical practice guidelines for health care providers and consumers.
The AIDSinfo Web site, located at AIDSinfo.nih.gov, is designed for full accessibility, ensuring easy search and navigation. The Web site presents federally approved information on HIV/AIDS treatment and prevention guidelines, a comprehensive database of both government and industry-supported HIV/AIDS clinical trials, and information about approved and experimental HIV/AIDS drugs, and vaccines. The site's Education and Resource Center is a virtual one-stop shop offering links and other downloadable resources specially designed for patients, researchers, health care providers, and the general public.
An AIDSinfo Telephone Help Line will provide access to English- and Spanish-speaking Health Information Specialists who offer confidential responses to questions, and assistance with navigating the Web site. The Help Line is available Monday through Friday, noon to 5:00 p.m., Eastern Time.
Telephone: 800-448-0440
International: 301-519-0459
TTY/TDD: 888-480-3739
E-mail: ContactUs@aidsinfo.nih.gov
AIDSinfo E-news, an electronic newsletter, will keep you informed about new and updated treatment guidelines, clinical trials, drugs, and Web site updates. If you already subscribe to the ATIS listserv, you will automatically be placed on the AIDSinfo E-news subscriber list. If not, please visit the AIDSinfo Web site on or after December 2 to subscribe.
Plan to visit the AIDSinfo Web site on or after December 2, or call to learn more about this exciting new service.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
FDA APPROVES NEW RAPID HIV TEST KIT
HHS Secretary Tommy G. Thompson today announced that the U.S. Food and Drug
Administration has approved a new rapid HIV diagnostic test kit that provides
results with 99.6 percent accuracy in as little as 20 minutes.
Using less than a drop of blood collected, this new test can quickly and reliably detect antibodies to HIV-1, the HIV virus that causes infection in most cases in the U.S. Unlike other antibody tests for HIV, this test can be stored at room temperature, requires no specialized equipment, and may be considered for use outside of traditional laboratory or clinical settings. The newly approved HIV test is called The OraQuick Rapid HIV-1 Antibody Test, manufactured by OraSure Technologies, Inc., Bethlehem, Pennsylvania.
"Each year, 8,000 HIV-infected people who come to public clinics for HIV testing do not return a week later to receive their test results," Secretary Thompson said. "With this new test, in less than a half an hour they can learn preliminary information about their HIV status, allowing them to get the care they need to slow the progression of their disease and to take precautionary measures to help prevent the spread of this deadly virus."
To perform the test, a fingerstick sample of blood is collected from an individual and transferred to a vial where it is mixed with a developing solution. The test device, which resembles a dipstick, is then inserted into the vial. In as little as 20 minutes, the test device will indicate if HIV-1 antibodies are present in the solution by displaying two reddish-purple lines in a small window on the device. Although the results of rapid screenings will be reported in point-of-care settings, as with all screening tests for HIV, if the OraQuick test gives a reactive test result, that result must be confirmed with an additional specific test. The OraQuick test has not been approved to screen blood donors.
FDA currently categorizes the OraQuick test as "moderate complexity" under the Clinical Laboratory Improvements Amendments of 1988 (CLIA). Under CLIA, new tests are categorized as either moderate or high complexity. This designation means that the OraQuik test can only be given in CLIA-approved labs by CLIA-certified laboratory technicians or medical staff. If the test manufacturer applies for a CLIA waiver, the FDA can evaluate it for use under less stringent conditions.
"I strongly urge the OraSure company to apply for a CLIA waiver," said Secretary Thompson, "If the FDA finds that the company's data proves that the OraQuick test is both easy and safe to use, it can get a CLIA waiver. Then the test could be given in many more health care settings, perhaps even administered by social workers in HIV counseling centers. But the process can't begin until OraSure applies for the waiver, so I ask them to please apply now!"
The Centers for Disease Control and Prevention (CDC) has estimated that one fourth of the approximately 900,000 HIV-infected people in the U.S. are not aware that they are infected. Because of the potential public health benefits of rapid HIV testing, the CDC and the Centers for Medicare and Medicaid Services (CMS) are working with state and other health officials to make the test widely available and to offer technical assistance and counseling training for its use.
"This test will be a great help in identifying pregnant HIV-infected women going into labor who were not tested during pregnancy so that precautionary steps can be take to block their newborns from being infected with HIV," said FDA Deputy Commissioner Dr. Lester M. Crawford. "It will also be a critical resource in helping identify HIV infection in health-care and emergency workers who are accidentally exposed to HIV-infected blood while doing their job."
Richard Klein
Office of Special Health Issues
Food and Drug Administration
This guidance is intended to assist sponsors in the clinical development of drugs for the treatment of human immunodeficiency virus (HIV) infection. Specifically, this guidance addresses the Agency's current thinking regarding designs of clinical trials that use HIV ribonucleic acid (RNA) measurements to support accelerated and traditional approvals of antiretroviral drug products. It is also intended to serve as a focus for continued discussions among the Division of Antiviral Drug Products (DAVDP), pharmaceutical sponsors, the academic community, and the public.
The draft version of this document, first posted in August 1999, was based on a DAVDP advisory committee meeting, convened in July 1997, to discuss the use of HIV RNA endpoints for traditional approval of antiretroviral drugs. This document has been updated to address public comments to the draft version and to include pertinent information from a DAVDP advisory committee meeting, convened in January 2001, to address issues relating to trial design in heavily treatment experienced HIV-infected patients.
This guidance does not address specific phase-1 and phase-2 development issues, development of alternate dosing regimens, or the use of HIV-1 resistance testing. These issues will be addressed separately in future guidance documents.
In addition to consulting guidance documents, sponsors are encouraged to contact the division to discuss specific issues that arise during the development of an antiretroviral drug product.
Accelerated approvals of antiretroviral drugs have been based for years on changes in surrogate endpoints, such as CD4 cell counts and plasma HIV RNA levels. Traditional approvals were based on clinical endpoint trials assessing the effects of a drug on mortality and/or HIV disease progression. With the availability of potent antiretroviral drug regimens and sensitive assays for assessing plasma HIV RNA, the standards of clinical practice evolved to a paradigm emphasizing maximal and durable HIV RNA suppression. In addition, with the successes of combination therapy and the subsequent decline of HIV-related illnesses (Palella et al., 1998; Hogg et al., 1999), it became clear that a requirement for clinical endpoint studies for every traditional approval was no longer necessary nor feasible.
In July 1997, the Agency convened an advisory committee meeting to consider the use of changes in HIV RNA levels as endpoints in clinical trials supporting traditional approval of antiretrovirals. To evaluate the feasibility of using HIV RNA levels as a study endpoint, a collaborative group of pharmaceutical, academic, and government scientists investigated relationships between treatment-induced changes in HIV RNA and clinical endpoints from ongoing and completed antiretroviral trials (Murray et al., 1999; Hill et al., 1998). In several analyses of more than 5000 patients in multiple trials, a clear association was identified between initial decreases in plasma HIV RNA levels and reduction in the risk of clinical progression and death. This relationship was observed across a range of patient characteristics including pretreatment CD4 counts and HIV RNA levels, prior drug experience, and treatment regimen. Based on these data, the Division of Antiviral Drug Products advisory committee concurred that treatment-induced decreases in HIV RNA levels were highly predictive of meaningful clinical benefit and that HIV RNA measurements could serve as endpoints in trials designed to support both accelerated and traditional approvals. The Division proposed that accelerated approvals could be based on studies that show a drug's contribution toward shorter-term reductions in HIV RNA (e.g., 24 weeks) while traditional approvals could be based on trials that show a drug's contribution toward durability of HIV RNA suppression (e.g., for at least 48 weeks). The committee agreed with this proposal and also recommended that changes in CD4 cell counts be consistent with observed HIV RNA changes when considering approval of an antiretroviral drug.
The guidance document can be accessed on the FDA website at:
http://www.fda.gov/cder/guidance/3647fnl.pdf
Richard Klein
Office of Special Health Issues
Food and Drug Administration
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Antiviral Drugs Advisory Committee; Notice of Meeting
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
This notice announces a forthcoming meeting of a public advisory committee of
the Food and Drug Administration (FDA). The meeting will be open to the public.
No registration is required.
Name of Committee: Antiviral Drugs Advisory Committee.
General Function of the Committee: To provide advice and recommendations to
the agency on FDA's regulatory issues.
Date and Time: The meeting will be held on November 14, 2002, from 8:30 a.m.
to 4 p.m.
Location: Holiday Inn, Versailles Ballroom, 8120 Wisconsin Avenue, Bethesda,
MD.*
Contact Person: Tara P. Turner, Pharm.D., Center for Drug Evaluation and Research
(HFD-21), Food and Drug Administration, 5600 Fishers Lane (for express delivery,
5630 Fishers Lane, Rm. 1093), Rockville, MD 20857, (301) 827-7001, e-mail: TurnerT@cder.fda.gov,
or FDA Advisory Committee Information Line, 1-800-741-8138 (301-443-0572 in
the Washington, DC area), code 12531. Please call the Information Line for up-to-date
information on this meeting.
Agenda: The committee will discuss biologics license application (BLA) 125061/0,
peginterferon alfa-2a co-packaged with ribavirin, new drug application (NDA)
21-511, Hoffmann-La Roche, Incorporated, proposed as combination therapy for
the treatment of chronic hepatitis C.
Procedure: Interested persons may present data, information, or views, orally
or in writing, on issues pending before the committee. Written submissions may
be made to the contact person by November 6, 2002. Oral presentations from the
public will be scheduled between approximately 1 p.m. and 2 p.m. Time allotted
for each presentation may be limited. Those desiring to make formal oral presentations
should notify the contact person before November 6, 2002, and submit a brief
statement of the general nature of the evidence or arguments they wish to present,
the names and addresses of proposed participants, and an indication of the approximate
time requested to make their presentation.
Persons attending FDA's advisory committee meetings are advised that the
agency is not responsible for providing access to electrical outlets.
FDA welcomes the attendance of the public at its advisory committee meetings
and will make every effort to accommodate persons with physical disabilities
or special needs. If you require special accommodations due to a disability,
please contact Tara Turner at least 7 days in advance of the meeting.
Notice of this meeting is given under the Federal Advisory Committee Act (5
U.S.C. app. 2).
*The hotel is located near the Washington Metro Red Line, Bethesda Station.
For hotel accommodations or directions, you can contact the Holiday Inn directly
at (301) 652-2000
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Pharmacokinetic data demonstrate that co-administration of VIREAD (tenofovir disoproxil fumarate) and VIDEX (Didanosine, ddI) resulted in significant increases in didanosine exposures; this information was included in the VIREAD label at the time it was initially approved. Recently the results of an interaction study of VIREAD and VIDEX EC were submitted and reviewed. Based on this new study, it was concluded that the magnitude of the interaction between VIREAD and VIDEX was significant enough to warrant additional precautionary language to be included in both products' labeling.
VIDEX BUFFERED TABLETS
Design
This was a Phase I, open-label, multiple-dose, crossover, and drug interaction
study. Eighteen otherwise healthy male and female subjects were randomized to
receive the following treatments in a random sequence: VIREAD 300 mg once daily
for 7 days, VIREAD 300 mg plus VIDEX TABS 250mg (wt < 60 kg) or 400 mg (wt
> 60 kg) once daily for 7 days, VIDEX TABS 250mg (wt < 60 kg) or 400 mg
(wt > 60 kg) once daily for 7 days with a 7-day washout between treatments.
VIREAD was administered 1 hour following VIDEX TABS, and both were administered
under fasted conditions. Samples for assessment of VIREAD and didanosine pharmacokinetics
were collected frequently throughout the study period.
Pharmacokinetic Results
The results demonstrated that VIREAD pharmacokinetics were not affected by co-administration
of VIDEX TABS. However, following co-administration, there were significant
increases in didanosine exposures (see Table 1).
Table 1. Effects of VIREAD on didanosine pharmacokinetics
| didanosine AUC (ng*hr/mL) | didanosine Cmax (ng/mL) |
|
|---|---|---|
| VIDEX TABS alone | 3560 | 2131 |
| VIDEX TABS+ VIREAD | 5167 (44%) | 2761 (28%) |
VIDEX EC
Design
This was an open-label, fixed-sequence, drug-drug interaction, and drug-food
interaction study conducted in 28 healthy volunteers. On day 1, subjects received
a single 400-mg dose of VIDEX EC following an overnight fast. On days 2-15 subjects
were dosed with VIREAD 300 mg with a light meal. On day 8, subjects took another
400-mg dose of VIDEX EC two hours prior to VIREAD. On day 9, subjects received
VIDEX EC and VIREAD simultaneously. Samples for assessment of VIREAD and didanosine
pharmacokinetics were collected frequently throughout the 15-day study period.
Pharmacokinetic Results
The results demonstrated that VIDEX EC had no effect on the pharmacokinetics
of VIREAD. However, either following simultaneous (fed) or staggered (fasted)
administration, there were significant increases in didanosine exposures (see
Table 2).
| didanosine AUC (ng*hr/mL) | didanosine Cmax (ng/mL) |
|
|---|---|---|
| VIDEX EC alone | 3160 | 1050 |
| VIDEX EC + TDF (simultaneous) | 4990 (60%) | 1720 (64%) |
| VIDEX EC (2 hours prior to TDF) |
4660 (48%) | 1560 (48%) |
Based on the results of these two interaction studies, The VIDEX and VIREAD labels have been revised as follows:
The pharmacokinetic results of both interaction studies are being added.
The following precautionary language has been added:
Exposure to didanosine or its active metabolite (dideoxyadenosine 5-triphosphate)
is increased when didanosine is co-administered with VIREAD. Increased exposure
may cause or worsen didanosine-related clinical toxicities, including pancreatitis,
symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Co-administration
of VIREAD with VIDEX should be undertaken with caution, and patients should
be monitored closely for didanosine-related toxicities. VIDEX should be suspended
if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic
acidosis develop (see WARNINGS).
Richard Klein
Office of Special Health Issues
Food and Drug Administration
The VIDEX (Didanosine, ddI) label has been revised to include new, precautionary information about co-administration of VIDEX and ribavirin (RBV) in HIV/HCV co-infected patients.
Literature reports (see 1, 2 below) and 24 cases submitted to the FDA Adverse Event Reporting System (AERS) were reviewed to examine cases of patients receiving VIDEX who added treatment with ribavirin. There appeared to be a relationship between the time that ribavirin was initiated and the occurrence of toxicity, on average 4.8 months.
In vitro data demonstrating that RBV increases the levels of the active Didanosine metabolite, dideoxyadenosine 5-triphosphate (ddATP), and clinical reports suggesting the potential for didanosine-related toxicities led to the addition of new precautionary language in the VIDEX label. The following has been added to the "Precautions" section of the label:
Exposure to didanosine or its active metabolite (dideoxyadenosine 5-triphosphate) is increased when didanosine is co-administered with ribavirin. Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Co-administration of ribavirin with VIDEX should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. VIDEX should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop.
1 Lafeuillade A, Hittinger G, Chadapaud S, The Lancet, Vol 357, Jan 27, 2001.
2 Salmon-Ceron D, Chauvelot-Moachon L, Abad S, et al., The Lancet, Vol 357, June 2, 2001.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
The Food and Drug Administration, on September 11, 2002, approved the VERSANT HIV-1 RNA 3.0 Assay (bDNA). This device is indicated for the direct quantitation of Human Immunodeficiency Virus Type 1 (HIV-1) in plasma of HIV-infected individuals.
The VERSANT® HIV-1 RNA 3.0 Assay (bDNA) is an in vitro signal amplification nucleic acid probe assay for the direct quantitation of human immunodeficiency virus type 1 (HIV-1) RNA in plasma of HIV-1 infected individuals using the Bayer® System 340 bDNA Analyzer. The test can quantitate HIV-1 RNA over the range of 75 - 500,000 HIV-1 RNA copies/mL. Plasma samples containing Group M Subtypes A - G have been validated for use in the assay.
This test is intended for use in conjunction with clinical presentation and other laboratory markers of disease status as an aid in management of individuals infected with HIV-1. HIV-1 RNA results from the assay can be used to assess prognosis of disease progression and to monitor the effects of antiretroviral therapy by measuring changes in HIV-1 RNA levels during the course of therapy. Monitoring the effects of antiretroviral therapy by serial measurements of plasma HIV-1 RNA has been validated for patients with viral loads ³ 25,000 copies/mL.
The VERSANT HIV-1 RNA 3.0 Assay (bDNA) is not intended for use as a screening assay for HIV infection or as a diagnostic test to confirm the diagnosis of HIV infection.
The VERSANT HIV-1 RNA 3.0 Assay is manufactured by Bayer Corporation of Berkeley, CA.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Return to Index
FDA APPROVES NEW TREATMENT FOR CHRONIC HEPATITIS B
The Food and Drug Administration (FDA) today announced the approval of Hepsera
(adefovir dipivoxil) tablets for the treatment of chronic hepatitis B in adults
with evidence of active viral replication and either elevations in serum alanine
aminotransferase (ALT) or aspartate aminotransferase (AST), or histologically
active disease.
Chronic hepatitis B is a serious disease caused by a virus that attacks the liver. The virus, which is called hepatitis B virus (HBV), can cause lifelong infection, cirrhosis (scarring) of the liver, liver cancer, liver failure, and death. According to the Centers for Disease Control and Prevention, approximately 1.25 million Americans are chronically HBV infected.
Hepsera slows the progression of chronic hepatitis B by interfering with viral replication and causing DNA chain termination after its incorporation into viral DNA.
FDA based its approval of Hepsera on the results of two randomized, double-blind, placebo-controlled studies. At week 48 of the studies, 53% of patients receiving Hepsera in one study and 64% of patients in the other study showed significant improvement in the liver inflammation caused by HBV compared to 25% and 35% of patients receiving placebo. A statistically significant improvement in the degree of liver fibrosis (scarring) was observed in the patients who received Hepsera. Moreover, Hepsera has been shown to be effective in treating patients with clinical evidence of HBV that is resistant to another approved antiviral therapy called lamivudine.
The major adverse events associated with the use of Hepsera include severe, acute exacerbation of hepatitis B after discontinuation of Hepsera and kidney toxicity. Patients who have discontinued other approved products for the treatment of chronic hepatitis B have also experienced severe, acute exacerbation of hepatitis. This adverse event occurred in up to 25% of clinical trial participants after discontinuation of Hepsera. The labeling for Hepsera states that patients who discontinue Hepsera should be monitored at repeated intervals over a period of time for hepatic function.
Kidney toxicity was reported in patients at risk of or having underlying kidney dysfunction.
In addition, there is a theoretical concern associated with Hepsera that HIV resistance could emerge in chronic hepatitis B patients with unrecognized or untreated HIV infection. Prior to initiating Hepsera therapy, HIV antibody testing should be offered to all patients. Hepsera (adefovir 10mg ) has not been shown to suppress HIV RNA in patients.
FDA's September 20, 2002 approval follows an August 6, 2002, recommendation by FDA's Antiviral Drugs Advisory Committee.
Gilead Sciences Inc., of Foster City, CA, is the sponsor of the approved New Drug Application (NDA) for Hepsera.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
We have received a number of inquiries related to the availability of nandrolone decanoate, the production of which had recently been discontinued in the United States. The decision to cease U.S, production was made by the manufacturer.
However, Watson (also known as Steris) is now producing nandrolone decanoate injection 100 mg/ml.
There is currently a limited supply of 100 mg/mL product and we anticipate that both the 100 mg/ml and 200 mg/ml strengths will be available by the end of October
The Watson customer service telephone number which may be used to order product is (800) 272-5525.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Please note that product labeling has been changed for AGENERASE (amprenavir)
Capsules and AGENERASE (amprenavir) Oral Solution to reflect new precautions
related to use of Agenerase with Methadone, and with oral (hormonal) contraceptives.
Methadone: Coadministration of amprenavir and methadone can decrease plasma
levels of methadone. AGENERASE may be less effective due to decreased amprenavir
plasma concentrations in patients taking these agents together. Alternative
antiretroviral therapy should be considered. Dosage of methadone may need to
be increased when coadministered with AGENERASE.
Oral contraceptives: (Ethinyl estradiol/norethindrone) Those taking AGENERASE
should be instructed not to use hormonal contraceptives because some birth control
pills (those containing ethinyl estradiol/norethindrone) have been found to
decrease the concentration of amprenavir. This may lead to loss of virologic
response and possible resistance to AGENERASE. Alternative methods of non-hormonal
contraception are recommended.
The complete Agenerase label may be found at
http://www.fda.gov/cder/foi/label/2002/21007s11,21039s10lbl.pdf
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Return to Index
SUCCESS OF PRIVATE SECTOR PATIENT INFORMATION WITH PRESCRIPTION MEDICINES ASSESSED
The Food and Drug Administration (FDA) announced the findings from a 2001 study
designed to assess the extent and usefulness of private sector prescription
information patients receive when filling their prescriptions. Study results
show approximately 89 percent of patients received written information about
the drugs prescribed for them.
FDA commissioned the study under the provisions of Public Law 104-180, which
was passed in 1996 and required the Department of Health and Human Services
to evaluate the adequacy of private sector prescription drug information given
to patients. The goal contained in that law was that 75 percent of patients
obtaining new prescriptions by the year 2000 receive useful written information.
The study, conducted by the National Association of Boards of Pharmacy to assess
the receipt and usefulness of patient information, reveals that 89 percent of
patients received written information.
Although this figure surpasses the goal of 75 percent, the overall usefulness
of information provided, as measured by 8 objective consensus-based criteria,
was about 50 percent. The scores for individual criteria varied, with the highest
scores (greater than 90 percent) showing that the information distributed was
scientifically accurate, up-to-date, and non-promotional.
Because the agency sees progress in meeting the goals set under Public Law 104-180,
FDA will continue to work with private sector partners to improve the usefulness
of patient information, and meet the goal for the year 2006, which calls for
95 percent of patients obtaining new prescriptions to receive useful written
medication information at the time of dispensing.
On July 17, 2002, the FDA's Drug Safety and Risk Management Advisory Committee will meet to discuss means to improve usefulness of consumer information. Background information for this meeting can be found on the FDA Internet site at:
http://www.fda.gov/ohrms/dockets/ac/02/briefing/3874b1.htm
For specific information about the advisory committee meeting, and how to submit data or express opinions on this topic, please call the FDA Advisory Committee Information Line at 1.800.741.8138, and use code no. 12535
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Return to Index
FDA approved on, June 26, 2002, a supplemental new drug application from GlaxoSmithKline expanding the labeled indication to provide for the use of Epivir (lamivudine) once daily for the treatment of HIV infection in combination with other antiretroviral agents, and a new 300 mg tablet. The product label has been modified to reflect these changes. The " Dosage and Administration" section of the label reads:
DOSAGE AND ADMINISTRATION:
Adults: The recommended oral dose of EPIVIR for adults is 300 mg daily, administered
as either
150 mg twice daily or 300 mg once daily, in combination with other antiretroviral
agents (see
DESCRIPTION OF CLINICAL STUDIES, PRECAUTIONS, MICROBIOLOGY, and CLINICAL
PHARMACOLOGY). If lamivudine is administered to a patient dually infected with
HIV and HBV, the dosage indicated for HIV therapy should be used as part of
an appropriate combination regimen (see WARNINGS).
A copy of the complete product label can be found at:
http://www.fda.gov/cder/approval/index.htm
by clicking "
E"
in the index and scrolling down to Epivir.
Label is dated 6/25/02
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Return to Index
Ortho Biotech Products, L.P., with the knowledge of FDA, notified pharmacists, health care providers, and wholesalers/distributors of counterfeit PROCRIT (epoetin alfa). Vials of PROCRIT labeled as 40,000 U/mL in four-pack boxes, lot number P002641, expiration date: 9/03, have been found to contain active ingredient that is approximately 20 times lower than would be expected for PROCRIT in 40,000 U/mL vials. Based on inventory and historic use patterns it is thought that all existing inventory of AUTHENTIC lot number P002641 may have been used. Any product bearing this lot number should be considered suspect and be closely examined. A brief description of the differences between the actual product and the counterfeit, with comparative photographs, is provided in the Ortho Biotech letter.
In addition lot number P002384, expiration: 03/2003 has also been determined to be counterfeit. Distinctions between this counterfeit lot and authentic PROCRIT are still being analyzed. Distinctions may not be the same as those identified in the Dear Healthcare Professional letter dated June 6, 2002. Thus, any product bearing this lot number in particular should be considered suspect.
PROCRIT is used primarily for the treatment of anemia associated with chemotherapy, chronic renal failure (pre-dialysis), zidovudine treatment in HIV patients, and patients undergoing elective, noncardiac, nonvascular surgery.
June 6, 2002 Letter - http://www.fda.gov/medwatch/SAFETY/2002/procrit.htm
June 6, 2002 Letter -
PDF format - ttp://www.fda.gov/medwatch/SAFETY/2002/ProcrittamperDDL.PDF
June 7, 2002 Letter - http://www.fda.gov/medwatch/SAFETY/2002/procrit2.htm
Ortho Biotech - PDF http://www.fda.gov/medwatch/SAFETY/2002/Procrittamper_UD.PDF
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Return to Index
Amgen, in cooperation with the FDA, notified pharmacists and health care providers
of counterfeit EPOGEN (epoetin alfa). Epogen is used to treat the anemia that
some patients with HIV/AIDS experience while taking zidovudine, commonly called
AZT.
EPOGEN 40,000 U/mL vials in ten-pack boxes, lot number P002970 expiration date:
7/03 has been found to contain active ingredient that is approximately 20 times
lower than would be expected for EPOGEN in 40,000 U/mL vials. Pharmacists and
health care providers should carefully examine all vials of EPOGEN before use.
A brief description and pictures of the differences between the actual product
and the counterfeit are provided.
For more information, read the MedWatch 2002 Safety Summary, including photos
and a link to the "
Dear Healthcare Professional"
letter, at:
http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#epogen
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Return to Index
Serono, Inc. became aware of a counterfeit lot of Serostim [somatropin (rDNA
origin) for injection]. The counterfeit material has been packaged to appear
as drug product lot number S810-1A1. This is not a legitimate Serostim lot
number. Preliminary information appears to indicate that the counterfeit
material may have been distributed via the Internet. However, pharmacists
should examine Serostim prior to dispensing to ensure that the package does
not bear lot number S810-1A1.
Patients should also check the product in their possession to ensure it does
not
bear the lot number S810-1A1.
You may access the MedWatch 2002 safety information summary, including links
to the
current press release, Dear Doctor Letter, and past MedWatch alerts regarding
Serostim, at:
http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#serost
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Return to Index
GlaxoSmithKline has received four reports of suspect bottles containing 60 tablets of Combivir (lamivudine plus zidovudine) that actually contained another medicine, Ziagen (abacavir sulfate) Tablets. The company has determined that counterfeit labels for Combivir Tablets were placed on two bottles of Ziagen and labels on another two bottles are suspect. Both medicines are used as part of combination regimens to treat HIV infection.
Pharmacists, physicians and patients should immediately examine the contents
of each Combivir bottle to confirm they do not contain Ziagen tablets. The two
kinds of tablets are easily distinguishable. Combivir is a white capsule-shaped
tablet engraved with "
GX FC3"
on one side; the other side of
the tablet is plain. Ziagen is a yellow capsule-shaped tablet engraved with
"
GX 623"
on one face; the other side is plain.
The risk to patients is primarily due to the fact that approximately 5% of individuals who receive abacavir sulfate in Ziagenâ or Trizivirâ (abacavir sulfate, lamivudine and zidovudine) Tablets have developed a potentially life-threatening hypersensitivity reaction. Symptoms generally resolve after discontinuing the medication, however, patients who have had a hypersensitivity reaction to Ziagenâ are advised to never take the medication again. Patients taking Combivirâ would not have been advised about the hypersensitivity reaction and how to take Ziagenâ safely because Combivirâ does not contain abacavir sulfate. Patients who have had a hypersensitivity reaction to abacavir yet take Ziagenâ or Trizivirâ again experience more severe symptoms within hours that may include life-threatening hypotension (lowering of the blood pressure) and death. In addition, the replacement of Combivirâ which contains two antiviral drugs with Ziagenâ , a single antiviral, may decrease the effectiveness of a patient's treatment regimen.
Read the MedWatch 2002 Safety Information Summary including links to the GlaxoSmithKline
press release at:
http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#comb
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Changes have been made in the WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and PATIENT INFORMATION sections of the ZERIT (stavudine, d4T) label to describe the occurrence of lactic acidosis and neuromuscular toxicity in patients using stavudine.
A total of 25 patients with neuromuscular weakness resembling Guillian-Barre syndrome in association with lactic acidosis were reported to the FDA's Adverse Event Reporting System. In most cases, antiretroviral therapy was continued in the presence of symptoms that might have been due to lactic acidosis, such as abdominal pain, nausea, and fatigue, leading to death in six of the patients. Most of these patients (22 out of 25) were receiving antiretroviral combinations containing stavudine. Although causality has not been established, these findings were consistent with recent reports in peer-reviewed journals that the use of stavudine in antiretroviral combination therapy may increase the risk of lactic acidosis. Therefore, the stavudine label now includes a warning that its use may increase the risk of lactic acidosis, which represents a rare, but serious adverse event. The label now includes the symptoms of the newly described symptomatic hyperlactemia syndrome, and the recommendation for prompt suspension of all antiretroviral therapy in suspected cases of lactic acidosis with or without neuromuscular weakness. Permanent discontinuation of stavudine should be considered in confirmed cases of lactic acidosis.
Please refer to the Zerit label for full prescribing information. A copy of
the revised labeling is available at:
http://www.fda.gov/cder/foi/label/2002/20412S017.pdf
Bristol-Myers Squibb Company, which makes and markets Zerit is distributing
a letter to health care providers giving more detailed information. The letter
reads:
February 2002
Dear Healthcare Provider,
Bristol-Myers Squibb Company would like to remind healthcare providers caring for persons with HIV of the potential for lactic acidosis as a complication of therapy with nucleoside analogues, including ZERIT (stavudine), d4T. The early signs and symptoms of clinical events associated with hyperlactatemia should receive careful attention because of the life-threatening potential of the most extreme manifestation, lactic acidosis syndrome (LAS).
Bristol-Myers Squibb has received reports of rare occurrences of rapidly ascending neuromuscular weakness, mimicking the clinical presentation of Guillain-Barré syndrome (including respiratory failure), in HIV-infected patients receiving stavudine in combination with other antiretrovirals. Some cases were fatal. Most of the cases were reported in the setting of lactic acidosis or symptomatic hyperlactatemia and, in most, antiretroviral therapy had been continued in the presence of non-specific signs compatible with early symptomatic hyperlactatemia that preceded the development of neuromuscular signs and symptoms. If motor weakness develops in a patient receiving stavudine, the drug should be discontinued.
Confirmed elevations of serum lactate may be associated with a broad spectrum of clinical manifestations, ranging from asymptomatic hyperlactatemia, through symptomatic non-acidotic hyperlactatemia (SHL), to acute severe LAS. Early signs and symptoms associated with a high lactate may be subtle and include generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and sudden unexplained weight loss), respiratory symptoms (tachypnea and dyspnea), or neurologic symptoms (including motor weakness). Patients with these symptoms should promptly interrupt antiretroviral therapy, and a full medical work-up should be performed rapidly.i Permanent discontinuation of stavudine should be considered for patients with confirmed LAS. It is important to note that symptoms associated with hyperlactatemia may continue or worsen following discontinuation of antiretroviral therapy.
At this time, prospective monitoring of lactate levels does not appear to be helpful in predicting the subsequent occurrence of SHL or LAS.i
Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing stavudine.ii, iii, iv
See the enclosed full prescribing information for ZERIT(r) for additional information regarding the recommended use of stavudine. If you have any further questions, please contact the Medical Information Department at Bristol-Myers Squibb Company at 1-800-426-7644.
Sincerely,
Michael R. Stevens, PharmD
Vice President, Medical Affairs, Virology
i. Brinkman K. Management of hyperlactatemia: no need for routine lactate measurements. AIDS 2001; 15: 795-797. ii. John M, Moore CB, James IR, et al. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS 2001; 15: 717-723. iii. Lonergan JT, Havlir D, Barber E, Mathews WC. Incidence and Outcome of Hyperlactatemia Associated with Clinical Manifestations in HIV-Infected Adults Receiving NRTI-Containing Regimens. 8th Conference on Retroviruses and Opportunistic Infections. Chicago, February 2001 [abstract 624]. iv. Gerard Y, Maulin L, et al. Symptomatic hyperlactatemia: an emerging complication of antiretroviral therapy. AIDS 2000; 14: 2723-2730.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
The FDA Safety Information and Adverse Event Reporting Program - Healthcare professionals are advised of a critical shortage of Cytovene-IV, indicated for the treatment or prevention of cytomegalovirus (CMV) disease.
This shortage in supply is expected to last through the second quarter of 2002. Roche Laboratories urges physicians to explore alternative treatment therapies or management strategies for their patients. This temporary situation affects only the IV formulation of Cytovene, and not the oral formulation of Cytovene (ganciclovir capsules).
Please see the MedWatch Safety alert at
http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#cytove
for details, including a link to a copy of the letter from Roche Laboratories.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration